Anti-HIV Activities and Mechanism of 12-O-Tricosanoylphorbol-20-acetate, a Novel Phorbol Ester from Ostodes katharinae

Abstract

APOBEC3G is a member of the human cytidine deaminase family that restricts Vif-deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC50 values ranged from 0.106 μM to 7.987 μM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection.

The Neuropeptides Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Control HIV-1 Infection in Macrophages Through Activation of Protein Kinases A and C

“…Because members of the APOBEC family can be targeted by PKA and PKC ( 22 – 24 ), it is possible that VIP and PACAP modulate these HIV-1 restriction factors, thus promoting mutations in the HIV-1 proviral DNA. To test this hypothesis, infected macrophages were treated with VIP or PACAP [or also IFN-α as a positive control, since it is a potent APOBEC3G inducer ( 47 )], and after 12 days, the mutation profile in the LTR region of the integrated provirus was analyzed.…”

“…In addition, some of these mutations carry the G-to-A APOBEC signature, and virus progeny from cultures exposed to PACAP have diminished replication fitness, which is also comparable to that induced by IFN-α. The mechanism responsible for these mutations could be a direct consequence of PACAP signaling as PKA and PKC can regulate the expression and activity of APOBEC family members and accessory factors ( 22 – 24 ). Of note, because we only analyzed the LTR region and because the hotspots for mutations are distributed in the entire HIV-1 genome ( 79 , 80 ), we expect that the mutation profile induced by VIP and PACAP represents a portion of a similar phenomenon that may have occurred in the HIV-1 genome as a whole.…”

“…VIP and PACAP are known to prevent the activity of some Cyclin/CDK complexes by increasing the production of their inhibitors ( 17 – 19 ) and are also capable of regulating the activity of NF-kB and NFAT ( 20 , 21 ). In addition, PKA and PKC phosphorylate and modulate the activity and transcription of APOBEC3G and other members of the APOBEC family, thus regulating the insertion of mutations into the HIV-1 genome ( 22 – 24 ). Therefore, VIP and PACAP may modulate the HIV-1 replication by controlling the availability of essential components for the establishment of a productive infection.…”

Plant-Based Natural Products and Extracts: Potential Source to Develop New Antiviral Drug Candidates

“…One of Hop-8′s mechanisms to resist infection by HIV verified in this study involves stimulating A3G expression, which prevents Vif-mediated degradation. This discovery may be considered as a potent strategy for therapeutic development in the future [ 68 ]. Other isolated natural compounds have been found to show significant anti-HIV properties ( Table 4 ) and may also be considered to serve as therapeutic agents.…”

APOBEC3s: history of an antiviral and mutagenic protein family

“…Plusieurs études ont eu pour objectif d'identifier des molécules capables d'inhiber (i) la dimérisation de Vif [197,354,355] ; (ii) l'interaction directe entre Vif et A3F/G [356][357][358] ; ou encore (iii) l'interaction de Vif avec les autres composants du VCBCC [359][360][361][362][363][364]. Une deuxième approche envisagée consiste à augmenter la concentration d'A3G dans les cellules infectées en stimulant son expression ou en augmentant sa stabilité, de façon à favoriser son incorporation dans les particules virales [365][366][367]. Enfin, une approche de type thérapie génique a récemment été proposée afin de rétablir l'activité antivirale naturelle des A3.…”